The paper reports the results of a feasibility study on the use of grazing incidence x-ray diffra... more The paper reports the results of a feasibility study on the use of grazing incidence x-ray diffraction (GIXRD) and synchrotron diffraction (GISRD) for near-surface characterisation of corrosion deposits induced by CO2 action on the inner surfaces of mild steel pipelines carrying natural gas. The principal direction of the diftkaction work, which forms part of a broader study, is to construct depth profiles of corrosion product phase distributions. Mild steel was corroded with a laboratory reactor in which the field corrosion conditions were simulated. GIXRD data for this preliminary study were measured with CuKa x-rays (h = 1.542 A), and the GISRD data with synchrotron radiation (A= 1.750 A) marginally lower in energy than the FeK-edge. The results show that the GIXRD at the stated wavelength, using either scanning detector optics or imaging plates, is promising for depth profile construction. It has been observed that GIXRD with imaging plates affords the possibility of conducting real-time GIXRD studies.
To study the nature of endotoxin or lipopolysaccharide (LPS) induced inflammation, we developed a... more To study the nature of endotoxin or lipopolysaccharide (LPS) induced inflammation, we developed a method of quantifying intracellular human neutrophil elastase (HNE) in lysed sputum polymorphs as a means to study the degranulation status of LPS-recruited neutrophils. Induced sputum, blood and exhaled nitric oxide (NO) were collected from 10 healthy non-atopic human subjects after inhaling a single 15 microg dose of Escherichia coil LPS in an open study. At 6 hours, LPS inhalation caused significant increase of sputum and blood neutrophils but without parallel increase in myeloperoxidase, HNE or interleukin-8 (IL-8) in sputum sol and blood, or exhaled NO. Intracellular HNE in lysed sputum polymorphs or purified blood neutrophils did not show any significant changes between inhaled LPS and saline, nor was there any appreciable change in percentage HNE release induced by N-Formyl-Met-Leu-Phe (fMLP) in vitro. We concluded that in healthy humans, the transient neutrophilic inflammation induced by a single dose of inhaled 15 microg LPS is mainly characterized by cell recruitment, not enhanced secretion of granular mediators or increased exhaled NO based on our experimental conditions.
Background: Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic respons... more Background: Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the airways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8, play an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule antagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2 antagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers. Methods: Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study. AZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and induced sputum was collected 6 h later. Results: Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79% reduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction in neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages (47%), leukotriene B 4 (39%) and CXCL8 (52%).
Proteomics is a powerful tool to ascertain which proteins are differentially expressed in the con... more Proteomics is a powerful tool to ascertain which proteins are differentially expressed in the context of disease. We have used this approach on inflammatory cells obtained from patients with asthma to ascertain whether novel drugs targets could be illuminated and to investigate the role of any such target in a range of in vitro and in vivo models of inflammation. A proteomic study was undertaken using peripheral blood mononuclear cells from mild asthmatic subjects compared with healthy subjects. The analysis revealed an increased expression of the intracellular kinase, mitogen activated protein kinase (MKK3), and the function of this protein was investigated further in preclinical models of inflammation using MKK3 knockout mice. We describe a 3.65 fold increase in the expression of MKK3 in CD8+ T lymphocytes obtained from subjects with asthma compared with healthy subjects using a proteomic approach which we have confirmed in CD8(+), but not in CD4(+) T lymphocytes or human bronchia...
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2014
CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects o... more CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses. To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses. In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's...
Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand, 2005
Sputum induction with nebulized hypertonic saline is increasingly being used to evaluate airway i... more Sputum induction with nebulized hypertonic saline is increasingly being used to evaluate airway inflammation. We investigated the procedure-associated risk in 16 asthmatics that were still symptomatic despite on high doses of regular corticosteroid (CS) therapy (7 on daily inhaled CS > or = 800 microg budesonide or equivalent; 9 on additional daily oral CS) and their sputum cellular profile. For comparison, 12 mild stable asthmatics and 10 normal healthy subjects were included. All subjects inhaled 3%, 4% and 5% hypertonic saline sequentially via ultrasonic nebulizer as a means to induce sputum. Maximal percentage fall of Forced Expiratory Volume on One Second (FEV1) during sputum induction was significantly greater in CS-dependent asthmatics (median % [IQR]: 16.0 [11.0-32.3]) than in mild asthmatics (5.3 [4.2-10.8], p = 0.002] and in normal subjects (4.6 [3.4-6.4]), p = 0.0001). The maximal percentage FEV1 fall was inversely correlated with baseline FEV1 (Rs= -0.69; p < 0.000...
American journal of orthopedics (Belle Mead, N.J.), 2003
Although there are many risk factors (such as age, family history, and obesity) associated with t... more Although there are many risk factors (such as age, family history, and obesity) associated with the development of osteoarthritis (OA), only trauma is known to cause OA. The neuromuscular system controls the amount and kind of movement occurring at a joint, so it is this system that is uitimately responsible for ensuring that joint tissues are not damaged to the point of developing OA during normal day-to-day activities. In the present paper, we review and critically evaluate some of the current concepts of the role of peripheral and central nervous system mechanisms that might protect joints from excessive excursion and joint tissues from excessive loading and OA. We conclude that a neuromuscular protective model based on central pattern generators (CPGs--subconscious motor programs) can best reconcile much heretofore ambiguous information pertaining to the development and progression of OA in stable and unstable joints.
Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vit... more Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown. The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an established early (EAR) and late asthmatic response (LAR) to allergen at screening received oral LY293111 in a dose of 112 mg three times daily for seven days or placebo before further allergen challenge. Each treatment was separated by a washout period of 28 days. Individuals underwent histamine challenge one hour before and three hours after allergen challenge. Bronchoalveolar lavage (BAL) fluid was obtained at bronchoscopy 24 hours after allergen challenge. There was no difference in baseline lung function, EAR, LAR, or in airway responsiveness to histamine before and after allergen between place...
Sumatriptan is effective in the acute treatment of migraine. However, about 15% of patients with ... more Sumatriptan is effective in the acute treatment of migraine. However, about 15% of patients with migraine do not experience headache relief after sumatriptan, and up to 40% may experience recurrence of headache within 24 hours. We studied whether pharmacokinetic or pharmacodynamic differences may explain these different clinical effects. We compared the pharmacokinetic profiles of subcutaneous sumatriptan in 14 patients who consistently had headache relief without headache recurrence, in 12 patients who had headache recurrence in every attack, and in six patients who did not have headache relief after sumatriptan. Because the antimigraine action of sumatriptan may be mediated through vasoconstriction of cranial blood vessels, we also compared in these patients changes in blood vessel diameter and blood velocity in the common, internal, and external carotid arteries. Despite sufficient power of the study, no important differences in pharmacokinetic and pharmacodynamic profiles betwee...
Journal of toxicology and environmental health, 1995
The chronic effects of secondary-treated effluent from a thermomechanical pulp (TMP) mill were as... more The chronic effects of secondary-treated effluent from a thermomechanical pulp (TMP) mill were assessed by means of long-term and short-term laboratory toxicity tests. The effluent used for the tests was sampled at a western Canadian mill using mostly softwoods and < 10% recycled fiber as furnish. In the long-term test, the effects of the effluent on the life cycle of fathead minnows (Pimephales promelas) were studied. In this experiment, which began with the egg stage and continued through to sexual maturity and reproduction, the fish were exposed in the laboratory to well water (control) and five concentrations (1.25%, 2.5%, 5%, 10%, or 20%) of effluent for 202 d. None of the effluent concentrations significantly affected the hatching of the eggs, the mortality, weight, length, gonad size, gender balance, and reproduction of the hatched fish, the prevalence of gross morphological and histopathological changes, and the hatchability of the first generation eggs. Two short-term te...
Proceedings of the American Society for Information Science and Technology, 2004
Information visualization is a rapidly evolving field of study involving many disciplines, such a... more Information visualization is a rapidly evolving field of study involving many disciplines, such as computer science, cognitive psychology, and of course information science. Historically, its research has synthesized, traversed, and recombined innovations from traditionally compartmentalized research areas. This panel will focus on future directions and historical trends of information visualization.
The paper reports the results of a feasibility study on the use of grazing incidence x-ray diffra... more The paper reports the results of a feasibility study on the use of grazing incidence x-ray diffraction (GIXRD) and synchrotron diffraction (GISRD) for near-surface characterisation of corrosion deposits induced by CO2 action on the inner surfaces of mild steel pipelines carrying natural gas. The principal direction of the diftkaction work, which forms part of a broader study, is to construct depth profiles of corrosion product phase distributions. Mild steel was corroded with a laboratory reactor in which the field corrosion conditions were simulated. GIXRD data for this preliminary study were measured with CuKa x-rays (h = 1.542 A), and the GISRD data with synchrotron radiation (A= 1.750 A) marginally lower in energy than the FeK-edge. The results show that the GIXRD at the stated wavelength, using either scanning detector optics or imaging plates, is promising for depth profile construction. It has been observed that GIXRD with imaging plates affords the possibility of conducting real-time GIXRD studies.
To study the nature of endotoxin or lipopolysaccharide (LPS) induced inflammation, we developed a... more To study the nature of endotoxin or lipopolysaccharide (LPS) induced inflammation, we developed a method of quantifying intracellular human neutrophil elastase (HNE) in lysed sputum polymorphs as a means to study the degranulation status of LPS-recruited neutrophils. Induced sputum, blood and exhaled nitric oxide (NO) were collected from 10 healthy non-atopic human subjects after inhaling a single 15 microg dose of Escherichia coil LPS in an open study. At 6 hours, LPS inhalation caused significant increase of sputum and blood neutrophils but without parallel increase in myeloperoxidase, HNE or interleukin-8 (IL-8) in sputum sol and blood, or exhaled NO. Intracellular HNE in lysed sputum polymorphs or purified blood neutrophils did not show any significant changes between inhaled LPS and saline, nor was there any appreciable change in percentage HNE release induced by N-Formyl-Met-Leu-Phe (fMLP) in vitro. We concluded that in healthy humans, the transient neutrophilic inflammation induced by a single dose of inhaled 15 microg LPS is mainly characterized by cell recruitment, not enhanced secretion of granular mediators or increased exhaled NO based on our experimental conditions.
Background: Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic respons... more Background: Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the airways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8, play an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule antagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2 antagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers. Methods: Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study. AZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and induced sputum was collected 6 h later. Results: Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79% reduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction in neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages (47%), leukotriene B 4 (39%) and CXCL8 (52%).
Proteomics is a powerful tool to ascertain which proteins are differentially expressed in the con... more Proteomics is a powerful tool to ascertain which proteins are differentially expressed in the context of disease. We have used this approach on inflammatory cells obtained from patients with asthma to ascertain whether novel drugs targets could be illuminated and to investigate the role of any such target in a range of in vitro and in vivo models of inflammation. A proteomic study was undertaken using peripheral blood mononuclear cells from mild asthmatic subjects compared with healthy subjects. The analysis revealed an increased expression of the intracellular kinase, mitogen activated protein kinase (MKK3), and the function of this protein was investigated further in preclinical models of inflammation using MKK3 knockout mice. We describe a 3.65 fold increase in the expression of MKK3 in CD8+ T lymphocytes obtained from subjects with asthma compared with healthy subjects using a proteomic approach which we have confirmed in CD8(+), but not in CD4(+) T lymphocytes or human bronchia...
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2014
CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects o... more CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses. To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses. In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's...
Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand, 2005
Sputum induction with nebulized hypertonic saline is increasingly being used to evaluate airway i... more Sputum induction with nebulized hypertonic saline is increasingly being used to evaluate airway inflammation. We investigated the procedure-associated risk in 16 asthmatics that were still symptomatic despite on high doses of regular corticosteroid (CS) therapy (7 on daily inhaled CS > or = 800 microg budesonide or equivalent; 9 on additional daily oral CS) and their sputum cellular profile. For comparison, 12 mild stable asthmatics and 10 normal healthy subjects were included. All subjects inhaled 3%, 4% and 5% hypertonic saline sequentially via ultrasonic nebulizer as a means to induce sputum. Maximal percentage fall of Forced Expiratory Volume on One Second (FEV1) during sputum induction was significantly greater in CS-dependent asthmatics (median % [IQR]: 16.0 [11.0-32.3]) than in mild asthmatics (5.3 [4.2-10.8], p = 0.002] and in normal subjects (4.6 [3.4-6.4]), p = 0.0001). The maximal percentage FEV1 fall was inversely correlated with baseline FEV1 (Rs= -0.69; p < 0.000...
American journal of orthopedics (Belle Mead, N.J.), 2003
Although there are many risk factors (such as age, family history, and obesity) associated with t... more Although there are many risk factors (such as age, family history, and obesity) associated with the development of osteoarthritis (OA), only trauma is known to cause OA. The neuromuscular system controls the amount and kind of movement occurring at a joint, so it is this system that is uitimately responsible for ensuring that joint tissues are not damaged to the point of developing OA during normal day-to-day activities. In the present paper, we review and critically evaluate some of the current concepts of the role of peripheral and central nervous system mechanisms that might protect joints from excessive excursion and joint tissues from excessive loading and OA. We conclude that a neuromuscular protective model based on central pattern generators (CPGs--subconscious motor programs) can best reconcile much heretofore ambiguous information pertaining to the development and progression of OA in stable and unstable joints.
Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vit... more Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown. The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an established early (EAR) and late asthmatic response (LAR) to allergen at screening received oral LY293111 in a dose of 112 mg three times daily for seven days or placebo before further allergen challenge. Each treatment was separated by a washout period of 28 days. Individuals underwent histamine challenge one hour before and three hours after allergen challenge. Bronchoalveolar lavage (BAL) fluid was obtained at bronchoscopy 24 hours after allergen challenge. There was no difference in baseline lung function, EAR, LAR, or in airway responsiveness to histamine before and after allergen between place...
Sumatriptan is effective in the acute treatment of migraine. However, about 15% of patients with ... more Sumatriptan is effective in the acute treatment of migraine. However, about 15% of patients with migraine do not experience headache relief after sumatriptan, and up to 40% may experience recurrence of headache within 24 hours. We studied whether pharmacokinetic or pharmacodynamic differences may explain these different clinical effects. We compared the pharmacokinetic profiles of subcutaneous sumatriptan in 14 patients who consistently had headache relief without headache recurrence, in 12 patients who had headache recurrence in every attack, and in six patients who did not have headache relief after sumatriptan. Because the antimigraine action of sumatriptan may be mediated through vasoconstriction of cranial blood vessels, we also compared in these patients changes in blood vessel diameter and blood velocity in the common, internal, and external carotid arteries. Despite sufficient power of the study, no important differences in pharmacokinetic and pharmacodynamic profiles betwee...
Journal of toxicology and environmental health, 1995
The chronic effects of secondary-treated effluent from a thermomechanical pulp (TMP) mill were as... more The chronic effects of secondary-treated effluent from a thermomechanical pulp (TMP) mill were assessed by means of long-term and short-term laboratory toxicity tests. The effluent used for the tests was sampled at a western Canadian mill using mostly softwoods and < 10% recycled fiber as furnish. In the long-term test, the effects of the effluent on the life cycle of fathead minnows (Pimephales promelas) were studied. In this experiment, which began with the egg stage and continued through to sexual maturity and reproduction, the fish were exposed in the laboratory to well water (control) and five concentrations (1.25%, 2.5%, 5%, 10%, or 20%) of effluent for 202 d. None of the effluent concentrations significantly affected the hatching of the eggs, the mortality, weight, length, gonad size, gender balance, and reproduction of the hatched fish, the prevalence of gross morphological and histopathological changes, and the hatchability of the first generation eggs. Two short-term te...
Proceedings of the American Society for Information Science and Technology, 2004
Information visualization is a rapidly evolving field of study involving many disciplines, such a... more Information visualization is a rapidly evolving field of study involving many disciplines, such as computer science, cognitive psychology, and of course information science. Historically, its research has synthesized, traversed, and recombined innovations from traditionally compartmentalized research areas. This panel will focus on future directions and historical trends of information visualization.
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Papers by Brian O'Connor